Multimode device and method for controlling breathing

ABSTRACT

A device and method is provided for therapeutic stimulating, augmenting, manipulating and/or controlling breathing, in combination with stimulation of auxiliary respiratory nerves or muscles including the upper airway tract, chest wall muscles or abdominal muscles. Stimulation may be provided, for example, to augment breathing or to prevent closing of the upper airway during therapeutic stimulation. Stimulation may be also provided to the Hypoglossal nerve during exhalation.

RELATED APPLICATION DATA

This application is a continuation in part of U.S. application Ser. No.11/271,726 filed Nov. 10, 2005 which is a continuation in part of U.S.application Ser. No. 10/966,484 filed Oct. 15, 2004; U.S. applicationSer. No. 10/966,474, filed Oct. 15, 2004; U.S. application Ser. No.10/966,421, filed Oct. 15, 2004; and U.S. application Ser. No.10/966,472 filed Oct. 15, 2004 which are continuations in part of U.S.application Ser. No. 10/686,891 filed Oct. 15, 2003 entitled: BREATHINGDISORDER DETECTION AND THERAPY DELIVERY DEVICE AND METHOD.

FIELD OF THE INVENTION

This invention relates to a device and method for treating respiratoryand related disorders.

BACKGROUND OF THE INVENTION

There are several factors believed to contribute to the occurrence ofobstructive respiratory events including anatomical deficiencies,deformities or conditions that increase the likelihood or occurrence ofupper airway collapse; ventilatory instability; and fluctuations in lungvolumes. There is believed to be a relationship between lung volume andthe aperture of the upper airway with larger lung volume leading togreater upper airway patency.

Some obstructive sleep apnea (OSA) patients have increased upper airwayresistance and collapsibility that may contribute to vulnerability toobstructive respiratory events. The pharyngeal airway is not supportedby bone or cartilaginous structure and accordingly relies on contractionof the upper airway dilator muscles to maintain patency. The pharyngealairway represents a primary site of upper airway closure.

Some OSA therapy has been based on a belief that OSA results from thesize and shape of the upper airway muscles or conditions such as obesitythat create a narrowing of the upper air passageway and a resultingpropensity for its collapse.

In patients with obstructive sleep apnea, various treatment methods anddevices have been used with very limited success.

CPAP machines have been used to control obstructive sleep apnea bycreating a continuous positive airway pressure (CPAP) at night. Externalventilatory control has been proposed including sensors that sense acessation of breathing to determine when an obstructive sleep apneaevent is occurring.

An implantable stimulator that stimulates the hypoglossal nerve aftersensing an episode of obstructive sleep apnea has been proposed but hasfailed to provide satisfactory results in OSA patients.

Treating OSA has primarily relied on continuous treatment or detectionof an obstructive respiratory event when it is occurring, i.e., when theupper air passageway has closed.

Drug therapy has not provided satisfactory results.

In central sleep apnea, as opposed to obstructive sleep apnea, it hasbeen proposed to stimulate a patient's diaphragm or phrenic nerve toinduce breathing where there is a lack of central respiratory drive.However, such therapy has be contraindicated for obstructive sleep apneaor respiratory events where there is an obstructive component, at leastin part because stimulating a patient to breathe when the airway isobstructed is believed to further exacerbate the collapsing of theairway passage by creating a pressure that further closes the airway.

Accordingly, it would be desirable to provide an improved device andmethod for treating OSA.

It would also be desirable to provide treatment for various otherrespiratory and related disorders.

SUMMARY OF THE INVENTION

The present invention provides a novel approach to treating obstructivesleep apnea and other respiratory related disorders or conditions.

In accordance with one aspect of the invention, in a patient diagnosedwith obstructive sleep apnea, tissue associated with the diaphragm orphrenic nerve is electrically stimulated to prevent obstructiverespiratory events.

In accordance with one aspect of the invention stimulation of thediaphragm or phrenic nerve is provided to such obstructive sleep apneapatients to reduce the occurrence of upper airway collapse or upperairway flow limitation.

In accordance with one aspect of the invention, a device and method forincreasing functional residual capacity (i.e., end expiratory lungvolume) is provided.

In accordance with one aspect of the invention, a device and method forincreasing upper airway patency is provided.

In accordance with one aspect of the invention, a device and method areprovided for providing ventilatory stability in an obstructive sleepapnea patient.

In accordance with one aspect of the invention, an indicator of animpending obstructive respiratory event is detected prior to eventonset.

In accordance with one aspect of the invention, a method for mitigating(i.e., preventing or lessening) obstructive respiratory events isprovided.

In accordance with one aspect of the invention, a method and device isprovided for synchronizing stimulation with one or more portions of anintrinsic breathing cycle.

In accordance with one aspect of the invention, a device and method foreliciting deep inspiration while avoiding airway closure are provided.

In accordance with one aspect of the invention, a device and method fornormalizing peak flow while increasing tidal volume are provided.

In accordance with one aspect of the invention, a device and method formanipulating exhalation are provided.

In accordance with one aspect of the invention, a device and method forentraining breathing are provided.

In accordance with another aspect of the invention, a device detectswhen an obstruction has occurred to a particular extent and refrainsfrom stimulating if the collapse has occurred to a particular extent.

In accordance with another aspect of the invention, a low level ofstimulation is provided for therapeutic effects.

In accordance with another aspect of the invention, a low level ofstimulation to the diaphragm or phrenic nerve is provided through orafter airway closure to speed up airway opening and reduce arousal.

In accordance with another aspect of the invention respiration iscontrolled by causing a diaphragm response in coordination withactivation of muscles associated with an upper airway of a subject.

In accordance with another object of the invention diaphragm stimulationtherapy is augmented or optimized by activating the upper airway musclesto improve tonicity of the airway during the diaphragm stimulation.

In accordance with another aspect of the invention, a device is providedthat will take over for a plurality of respiratory control functions.Such plurality of functions may include, for example, diaphragm controlin coordination with upper airway control. The functions are controlledby providing an electrically stimulating signal that elicits a diaphragmresponse in combination with an electrically stimulating signal thatcontrols the upper airway in a coordinated manner. The device may alsocontrol chest wall or abdominal muscles in combination with diaphragmcontrol and/or upper airway control, in order to augment respirationand/or optimize intrapleural volume during diaphragm stimulation suchas, e.g., a low level or bias stimulation.

According to another aspect of the invention, at least two groups ofmuscles associated with respiration may be controlled or coordinated.These groups may include diaphragm related muscles, chest wall relatedmuscles, abdominal muscles and/or upper airway related muscles

These and other inventions are described herein and/or set forth in theclaims herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of a device implanted in a subjectin accordance with the invention.

FIG. 1B is a schematic illustration of a device implanted in a subjectin accordance with the invention.

FIG. 2 is a schematic illustration of a processor unit of a sleepbreathing disorder treatment device in accordance with the invention.

FIG. 3 is a schematic illustration of an external device of a stimulatorin accordance with the invention.

FIG. 4A is a schematic illustration of respiration of an exemplaryobstructive sleep apnea patient as the patient is going into anobstructive sleep apnea event.

FIG. 4B is a schematic illustration of respiration of an exemplaryobstructive sleep apnea patient as the patient is going into anobstructive sleep apnea event.

FIGS. 4C and 4D are schematic illustrations respectively of respirationresponse and stimulation waveforms illustrating a stimulation methodusing a stimulation device according to the invention in which theobstructive sleep apnea event illustrated in FIG. 4A is treated withdeep inspiration stimulation.

FIG. 5A is a schematic illustration of respiration of an exemplaryobstructive sleep apnea patient as the patient is going into anobstructive sleep apnea event.

FIGS. 5B and 5C are schematic illustrations respectively of respirationresponse and stimulation waveforms illustrating a stimulation methodusing a stimulation device according to the invention in which theobstructive sleep apnea event illustrated in FIG. 5A is treated withdeep inspiration stimulation.

FIGS. 6A, 6B and 6C are schematic illustrations respectively of airflow,tidal volume and corresponding stimulation waveforms illustrating astimulation method using a stimulation device according to the inventionin which stimulation is applied during a portion of the respirationcycles.

FIGS. 7A and 7B are schematic illustrations respectively of tidal volumeand corresponding stimulation waveforms illustrating a stimulationmethod using a stimulation device according to the invention in whichstimulation is applied during a portion of the respiration cycles.

FIGS. 8A and 8B are schematic illustrations respectively of tidal volumeand corresponding stimulation waveforms illustrating a stimulationmethod using a stimulation device in which stimulation is applied inaccordance with the invention.

FIGS. 9A, 9B and 9C are schematic illustrations respectively of airflow,tidal volume and corresponding stimulation waveforms illustrating astimulation method using a stimulation device in which stimulation isapplied in accordance with the invention.

FIGS. 10A, 10B and 10C are schematic illustrations respectively ofairflow, tidal volume and corresponding stimulation waveformsillustrating a stimulation method using a stimulation device in whichstimulation is applied in accordance with the invention.

FIGS. 11A and 11B are schematic illustrations respectively ofrespiration response and stimulation waveforms illustrating astimulation method using a stimulation device according to theinvention.

FIGS. 12A, 12B and 12C are schematic illustrations respectively of flowand tidal volume respiration response and stimulation waveformsillustrating a stimulation method using a stimulation device accordingto the invention.

FIGS. 13A and 13B are schematic illustrations respectively ofrespiration response and stimulation waveforms illustrating astimulation method using a stimulation device according to theinvention.

FIGS. 14A and 14B are schematic illustrations respectively ofrespiration response and stimulation waveforms illustrating astimulation method using a stimulation device according to theinvention.

FIG. 15 is a flow chart illustrating operation of a device in accordancewith the invention.

FIG. 16A is a schematic of a signal processor of the processor unit inaccordance with the invention.

FIG. 16B is a schematic example of a waveform of an integrated signalprocessed by the signal processor of FIG. 16A.

FIG. 16C is a schematic EMG envelope waveform.

FIG. 16D is a schematic waveform corresponding to or correlated with airflow.

FIG. 16E is a schematic waveform correlated to intrapleural pressure.

FIGS. 17A, 17B, 17C, 17D and 17E are schematic illustrationsrespectively of diaphragm EMG envelope; flow or inverse of upper airwaypressure; tidal volume or inverse of intrapleural pressure;corresponding diaphragm stimulation; and corresponding hypoglossalstimulation illustrating a stimulation method using a stimulation devicein which stimulation is applied in accordance with the invention.

FIGS. 18A, 18B, 18C, 18D, 18E and 18F are schematic illustrationsrespectively of diaphragm EMG envelope; flow or inverse of upper airwaypressure; tidal volume or inverse of intrapleural pressure;corresponding diaphragm stimulation; and corresponding hypoglossalstimulation illustrating a stimulation method using a stimulation devicein which stimulation is applied in accordance with the invention.

FIGS. 19A, 19B, 19C, 19D and 19E are schematic illustrationsrespectively of diaphragm EMG envelope; flow or inverse of upper airwaypressure; tidal volume or inverse of intrapleural pressure;corresponding diaphragm stimulation; and corresponding hypoglossalstimulation illustrating a stimulation method using a stimulation devicein which stimulation is applied in accordance with the invention.

FIGS. 20A, 20B, 20C, 20D and 20E are schematic illustrationsrespectively of diaphragm EMG envelope; flow or inverse of upper airwaypressure; tidal volume or inverse of intrapleural pressure;corresponding diaphragm stimulation; and corresponding hypoglossalstimulation illustrating a stimulation method using a stimulation devicein which stimulation is applied in accordance with the invention.

FIG. 21 is a schematic illustration of a device or system according tothe invention.

DETAILED DESCRIPTION

In accordance with one aspect of the invention, a method and device fortreating obstructive sleep apnea patients is provided. According to oneembodiment, a device is provided that manipulates breathing according toone or more protocols, by stimulating the diaphragm or phrenic nerve tomitigate or prevent obstructive respiratory events including obstructivesleep apnea or other events with an obstructive component. The devicemay comprise a phrenic nerve or diaphragm stimulator and a sensorconfigured to sense a condition of a subject indicating a possibilitythat an obstructive respiratory event will occur or is occurring. Inaccordance with the invention, obstructive respiratory events arecharacterized by a narrowing of the air passageway, typically the upperair passageway. Examples of obstructive respiratory events include butare not limited to obstructive sleep apnea, obstructive hypopnea andother respiratory events with an obstructive component.

In another embodiment, stimulation is applied at a low level through orafter an obstructive respiratory event has occurred.

In addition, in accordance with the invention stimulation techniques forcontrolling or manipulating breathing may be used for therapeuticpurposes in other non-OSA patients.

In addition, in accordance with the invention stimulation techniques forcontrolling or manipulating breathing may coordinate stimulating adiaphragm response with controlling upper airway muscles.

FIGS. 1A and 2 illustrate a stimulator 20 comprising electrodeassemblies 21, 22, each comprising a plurality of electrodes 21 a-d and22 a-d respectively. The electrode assemblies 21, 22 are implanted inthe diaphragm muscle so that one or more of electrodes 21 a-d and ofelectrodes 22 a-d are approximately adjacent to one or more junctions ofthe phrenic nerves 15, 16, respectively, with the diaphragm 18 muscle.Alternatively or additionally, electrodes or electrode assemblies may beimplanted on the diaphragm from the thoracic side, at a location alongthe phrenic nerve in the thoracic region, neck region or other locationadjacent a phrenic nerve (e.g. transvenously) where stimulating thephrenic nerve affects breathing and/or diaphragm movement of thesubject. In addition, leads may be subcutaneously placed to stimulate atleast a portion of the diaphragm or phrenic nerve. The electrodeassemblies 21, 22, 31, 32, 41, 42 described herein are coupled tooutputs of a pulse generator and are configured to deliver electricallystimulating signals to tissue associated with the implanted electrodeassemblies.

The electrode assemblies 21, 22 (31, 32, 41, 42) may sense as well aspace or electrically stimulate at the diaphragm muscle or at the phrenicnerve. Electrode 51 may stimulate (as well as sense) at the upper airwaymuscles or hypoglossal nerve. Electrode 58 may stimulate (as well assense) at the chest wall muscles or associated nerves. Electrode 59 maystimulate (as well as sense)at the abdominal muscles or associatednerves. Electrode assemblies 21, 22 may be implanted laparoscopicallythrough the abdomen and into the muscle of the diaphragm 18 withneedles, tissue expanding tubes, cannulas or other similar devices. Theelectrode assemblies 21, 22 may be anchored with sutures, staples, orother anchoring mechanisms. The electrode assemblies 21, 22 may besurface electrodes or alternatively intramuscular electrodes. The leads23, 24 coupling the electrode assemblies 21, 22 to the control unit 100are routed subcutaneously to the side of the abdomen where asubcutaneous pocket is created for the control unit 100. The electrodeassemblies 21, 22 are each flexible members with electrodes 21 a-d,assembled about 1-20 mm apart from one another and electrodes 22 a-dassembled about 1-20 mm apart from one another. The electrode assemblies21, 22 are coupled via leads 23, 24 to control unit 100. The stimulator20 further comprises one or more sensors configured to sense one or morephysiologic parameters. For example one or more sensors such as anaccelerometer or movement sensor may sense information regardingmovement pattern of the diaphragm muscles, intercostal muscles, and ribmovement and thus determine overall respiratory activity and patterns.An electrode or electrodes may be used to sense the EMG of the diaphragmto determine respiration parameters. A flow sensor may be implanted inor near the trachea to sense tracheal air flow. A flow sensor 56 may beimplanted in or near the mouth. An intrapleural pressure sensor 57 maybe implanted on the top side of the diaphragm on its own or with one ormore electrode assemblies 21, 22. The various sensors may beincorporated with electrode assemblies 21, 22, or may be separatelyimplanted or otherwise coupled to the subject.

The control unit 100 is configured to receive and process signalscorresponding to sensed physiological parameters, e.g., pressure, flow,nerve activity, diaphragm or intercostal muscle movement, and/or EMG ofthe diaphragm 18, to determine the respiratory parameters of thediaphragm 18. An EMG signal may be used or other sensed activity mayalso correspond with either tidal volume or airflow and may be used toidentify different portions of a respiration cycle. An example of suchsignal processing or analysis is described in more detail herein withreference to a sensed respiration correlated signal, such as an EMG,flow, pressure or tidal volume correlated signal, in FIGS. 16A-16D.

The electrodes assemblies 21, 22 are coupled via leads 23, 24 toinput/output terminals 101, 102 of a control unit 100. The leads 23, 24comprise a plurality of electrical connectors and corresponding leadwires, each coupled individually to one of the electrodes 21 a-d, 22a-d. Alternatively or in addition, electrodes 31, 32 implanted on ornear the phrenic nerve in the thoracic region or electrodes 41, 42implanted on or near the phrenic nerve in the neck region. Otherlocations at or near the phrenic nerve may be stimulated as well.Electrode(s) 51, may be placed at or near the hypoglossal nerve inaccordance with a variation of the invention where stimulation of thediaphragm is coordinated with activation of upper airway muscles to openthe airway passage just prior to stimulating the diaphragm muscles.Electrode(s) 51 is (are) coupled through lead(s) 52 to electronics incontrol unit 100. Control unit 100 is also configured to receiveinformation from one or more sensors, including, for example upperairway pressure sensor 56 or intrapleural pressure sensor 57.Alternatively or in addition, electrode(s) 58 may be implanted at ornear the chest wall muscles or associated nerves and may be used tostimulate chest wall muscles in coordination with diaphragm stimulation.According to one aspect, the chest wall stimulation may augmentdiaphragm stimulation to enhance breathing or lung volume control.Alternatively or in addition, electrode(s) 59 may be implanted at ornear one or more abdominal muscle groups or associated nerves and may beused to stimulate abdominal muscles in coordination with diaphragmstimulation. According to one aspect, the abdominal muscle stimulationmay augment diaphragm stimulation to enhance breathing or lung volumecontrol.

The control unit 100 is implanted subcutaneously within the patient, forexample in the chest region on top of the pectoral muscle. The controlunit may be implanted in other locations within the body as well. Thecontrol unit 100 is configured to receive sensed nerve electricalactivity from the sensors or electrode assemblies 21, 22, (31, 32, 41,42, 51, 57, 58, 59) corresponding to respiratory effort or otherrespiration related parameters of a patient. The control unit 100 isalso configured to receive information corresponding to otherphysiological parameters as sensed by other sensors. The control unit100 delivers stimulation to the nerves 15, 16 or diaphragm as desired inaccordance with the invention. The control unit 100 also deliversstimulation to the hypoglossal nerve 19. The control unit 100 maydetermine when to stimulate the diaphragm and/or hypoglossal nerve, aswell as specific stimulation parameters, e.g., based on sensedinformation. The control unit 100 may determine when to stimulate thechest wall or abdominal muscles, as well as specific stimulationparameters, e.g., based on sensed information.

Additional sensors may comprise movement detectors 25, 26, in thisexample, strain gauges or piezo-electric sensors included with theelectrode assemblies 21, 22 respectively and electrically connectedthrough leads 23, 24 to the control unit 100. The movement detectors 25,26 detect movement of the diaphragm 18 and thus the respirationparameters. The movement detectors 25, 26 sense mechanical movement anddeliver a corresponding electrical signal to the control unit 100 wherethe information is processed by the processor 105. The movementinformation correlates to airflow and may accordingly be used todetermine related respiration parameters. Upper airway pressure sensor56 is positioned for example in the mouth or trachea and provides asignal that may be correlated to flow inverse of flow. Intrapleuralpressure sensor 57 provides a signal that is schematically illustratedin FIG. 16E and is generally correlated to the inverse of tidal volume.The signal from the positive airway pressure sensor and the intrapleuralpressure sensor may be processed and used for example, as described withrespect to FIGS. 16A and 16B.

Electrodes may be selected from the plurality of electrodes 21 a-d and22 a-d once implanted, to optimize the stimulation response. Electrodesmay also be selected to form bipolar pairs or multipolar groups tooptimize stimulation response. Alternatively electrodes may be in amonopolar configuration. Testing the response may be done by selectingat least one electrode from the electrodes in an assembly or any othercombination of electrodes to form at least one closed loop system, byselecting sequence of firing of electrode groups and by selectingstimulation parameters. The electrodes may be selected by an algorithmprogrammed into the processor that determines the best location andsequence for stimulation and/or sensing nerve and/or EMG signals, e.g.,by testing the response of the electrodes by sensing respiratory effortor flow in response to stimulation pulses. Alternatively, the selectionprocess may occur using an external programmer that telemetricallycommunicates with the processor and instructs the processor to causestimulation pulses to be delivered and the responses to be measured.From the measured responses, the external programmer may determine theoptimal electrode configuration, by selecting the electrodes to have anoptimal response to delivery of stimulation.

Alternative mapping techniques may be used to place one or morestimulation electrodes on the diaphragm. Examples of mapping thediaphragm and/or selecting desired locations or parameters for desiredstimulation responses are described for example in U.S. application Ser.No. 10/966,484 filed Oct. 15, 2004 and entitled: SYSTEM AND METHOD FORMAPPING DIAPHRAGM ELECTRODE SITES; in U.S. application Ser. No.10/966,474, filed Oct. 15, 2004 entitled: BREATHING THERAPY DEVICE ANDMETHOD; in U.S. application Ser. No. 10/966,472 filed Oct. 15, 2004entitled: SYSTEM AND METHOD FOR DIAPHRAGM STIMULATION; U.S. applicationSer. No. 10/966,421 filed Oct. 15, 2004 entitled: BREATHING DISORDER ANDPRECURSOR PREDICTOR AND THERAPY DELIVERY DEVICE AND METHOD; and in U.S.application Ser. No. 10/686,891 filed Oct. 15, 2003 entitled BREATHINGDISORDER DETECTION AND THERAPY DELIVERY DEVICE AND METHOD, all of whichare fully incorporated herein by reference.

FIG. 1B illustrates an alternative positioning of a stimulator 20′ inaccordance with the invention. Electrodes 21′ and 22′ aremicrostimulating electrodes positioned on or adjacent the phrenic nervebranches 15, 16 respectively. Electrodes 21′, 22′ are in telemetriccommunication with the control unit 100′. Alternatively, electrodes 21′,22′ may be nerve cuff electrodes or other electrodes coupled by a leadto the control unit 100′. Electrode 51′ also may either be amicrostimulating electrode in telemetric communication with the controlunit 100′ or may be coupled via a lead to control unit 100′. Controlunit 100′ and electrodes 21′, 22′ and 51′ operate to control breathingin a manner similar to that described with respect to electrodeassemblies 21, 22, electrode 51 and control unit 100 herein.

Any of the electrodes described in this application may be powered by anexternal source, e.g., an external control unit. Additionally, any ofthe electrodes herein may be microstimulators, including, for example,implanted microstimulators with electronic circuitry; and an externalpower source, e.g. an RF coupled source.

FIG. 2 illustrates an implantable control unit 100. The control unit 100includes electronic circuitry capable of generating and/or deliveringelectrical stimulation pulses to the electrodes or electrode assemblies21, 22, 31, 32, 41, 42, through leads 23, 24, 33, 34, 43, 44,respectively, to cause a diaphragm respiratory response in the patient.The control unit 100 electronic circuitry is also configured to generateand/or deliver electrical stimulation to electrode 51, through lead 52,to cause an upper airway response such as increased tonicity and/oropening of upper airway (electrode 51 may also comprise a pair ofbipolar electrodes). For purposes of illustration, in FIG. 2, thecontrol unit 100 is shown coupled through leads 23, 24 to electrodeassemblies 21, 22 respectively. Other leads as described herein may beconnected to inputs 101, 102 or other inputs.

The control unit 100 comprises a processor 105 for controlling theoperations of the control unit 100. The processor 105 and otherelectrical components of the control unit are coordinated by an internalclock 110 and a power source 111 such as, for example a battery sourceor an inductive coupling component configured to receive power from aninductively coupled external power source. The processor 105 is coupledto a telemetry circuit 106 that includes a telemetry coil 107, areceiver circuit 108 for receiving and processing a telemetry signalthat is converted to a digital signal and communicated to the processor105, and a transmitter circuit 109 for processing and delivering asignal from the processor 105 to the telemetry coil 107. The telemetrycoil 107 is an RF coil or alternatively may be a magnetic coil. Thetelemetry circuit 106 is configured to receive externally transmittedsignals, e.g., containing programming or other instructions orinformation, programmed stimulation rates and pulse widths, electrodeconfigurations, and other device performance details. The telemetrycircuit is also configured to transmit telemetry signals that maycontain, e.g., modulated sensed and/or accumulated data such as sensedEMG activity, sensed flow or tidal volume correlated activity, sensednerve activity, sensed responses to stimulation, sensed positioninformation, sensed movement information and episode counts orrecordings.

The leads 23, 24 are coupled to inputs 101, 102 respectively, of thecontrol unit 100, with each lead 23, 24 comprising a plurality ofelectrical conductors each corresponding to one of the electrodes orsensors (e.g., movement sensor) of the electrode assemblies 23, 24. Thusthe inputs 101, 102 comprise a plurality of inputs, each inputcorresponding to one of the electrodes or sensors. The signals sensed bythe electrode assemblies 21, 22 are input into the control unit 100through the inputs 101, 102. Each of the inputs are coupled to aseparate input of a signal processing circuit 116 (schematicallyillustrated in FIG. 2 as one input) where the signals are thenamplified, filtered, and further processed, and where processed data isconverted into a digital signal and input into the processor 105. Eachsignal from each input is separately processed in the signal processingcircuit 116.

The EMG/Phrenic nerve sensing has a dual channel sensor. Onecorresponding to each lung/diaphragm side. However, sensing can beaccomplished using a single channel as the brain sends signals to theright and left diaphragm simultaneously. Alternatively, the EMG orphrenic nerve collective may be sensed using a single channel. Either adual channel or single channel setting may be used and programmed.

The control unit 100 further includes a ROM memory 118 coupled to theprocessor 105 by way of a data bus. The ROM memory 118 provides programinstructions to the control unit 100 that direct the operation of thestimulator 20. The control unit 100 further comprises a first RAM memory119 coupled via a data bus to the processor 105. The first RAM memory119 may be programmed to provide certain stimulation parameters such aspulse or burst morphology; frequency, pulse width, pulse amplitude,duration and a threshold or trigger to determine when to stimulate. Thefirst RAM may also be programmed to provide coordination of stimulationto the diaphragm/phrenic nerve with the upper airway/hypoglossal nerve,chest wall muscles/nerves or abdominal muscles/nerves. A second RAMmemory 120 (event memory) is provided to store sensed data sensed, e.g.,by the electrodes of one or more electrode assemblies 21, 22 (EMG ornerve activity), position sensor 121, diaphragm movement sensors orstrain gauges 25, 26, or the accelerometer 122 or other sensors such asa flow or tidal volume correlated sensors (e.g. using movement sensorsor impedance plethysmography with a sensor positioned at one or morelocations in the body such as on the control unit 100. These signals maybe processed and used by the control unit 100 as programmed to determineif and when to stimulate or provide other feedback to the patient orclinician. Also stored in RAM memory 120 may be the sensed waveforms fora given interval, and a count of the number of events or episodes over agiven time as counted by the processor 105. The system's memory will beprogrammable to store information corresponding to breathing parametersor events, stimulation delivered and responses, patient compliance,treatment or other related information. These signals and informationmay also be compiled in the memory and downloaded telemetrically to anexternal device 140 when prompted by the external device 140.

An example of the circuits of the signal processing circuit 116corresponding to one or more of the sensor inputs is illustratedschematically in FIG. 16A. A sensor input signal correlating orcorresponding to EMG, tidal volume or flow is input into an amplifier130 that amplifies the signal. The signal is then filtered to removenoise by filter 131. The amplified signal is rectified by a rectifier132, is converted by an A/D converter 133 and then is integrated byintegrator 134 to result in an integrated signal from which respiratoryinformation can be ascertained. A flow correlated signal may be inputthrough A/D converter 133 a and then input through the integrator 134. Asignal corresponding to upper airway (or epiglossal) pressure may alsobe used as a flow correlated signal by inverting an upper airwaypressure signal with inverter 133 b and inputting the signal through A/Dconverter 133 a. The signal output of the integrator 134 is then coupledto the processor 105 and provides a digital signal corresponding to theintegrated waveform to the processor 105. A tidal volume correlatedsignal or an intrapleural pressure correlated signal may also be inputto the signal processing circuit through A/D converter 134 a at theoutput of the integrator 134. Intrapleural pressure may first beinverted through inverter 134 b before inputting into A/D converter 134a. The signal output of the integrator 134 is coupled to a peak detector135 that determines when the inspiration period of a respiratory cyclehas ended and an expiration cycle has begun. The signal output of theintegrator 134 is further coupled to a plurality of comparators 136,137. The first comparator 136 determines when respiration has beendetected based on when an integrated signal waveform amplitude has beendetected that is greater than a percentage value of the peak of anintrinsic respiratory cycle or another predetermined amount (comp 1),for example between 1-25% of the intrinsic signal. In this example, thecomparator is set at a value that is 10% of the waveform of an intrinsicrespiratory cycle. The second comparator 137 determines a value of thewaveform amplitude (comp 2) when an integrated signal waveform amplitudehas been detected that is at a predetermined percentage value of thepeak of an intrinsic respiratory cycle or another predetermined amount,for example between 75%-100% of the intrinsic signal. In this example,the comparator is set at a value that is 90% of the waveform of anintrinsic respiratory cycle. From this value and the comp 1 value, theslope of the inspiration period (between 10% and 90% in this example)may be determined. This slope may provide valuable diagnosticinformation as it shows how quickly a patient inhales.

In the case of a signal correlating to flow that is integrated or asignal correlated to tidal volume, after (or when) the peak detectordetects the end of an inhalation period and the beginning of anexhalation period, the third comparator 138 determines an upper valuefor the waveform amplitude during active exhalation period, for examplebetween 100% and 75% of the peak value detected by the peak detector135. Then a lower value (comp 4) of the waveform during the exhalationperiod is determined by the fourth comparator 139, which compares themeasured amplitude to a predetermined value, e.g. a percentage value ofthe peak amplitude. In this example, the value is selected to be 10% ofthe peak value. In one embodiment this value is selected to roughlycoincide with the end of a fast exhalation period. From comp 3 and comp4 values, the slope of the exhalation period (between 10% and 90% inthis example) may be determined. This slope may provide valuablediagnostic information as it shows how quickly a patient exhales.

A non-integrated flow signal may also be used, for example inconjunction with EMG to detect airway closure where EMG is present inthe absence of flow. An upper airway pressure signal is correlated withflow, so the absence of negative deflection corresponding to inhalationindicates airway closure.

The intrapleural pressure signal is generally the inverse of tidalvolume. Intrapleural pressure may be used to provide diagnosticinformation such as lung volume information, duration of respiratorycycles, and rate of inhalation and exhalation.

Intrapleural pressure may be used by setting threshold levels used todetermine different phases of a respiration cycle. For example, thenegative peak 175 a of intrapleural pressure correlates generally withthe start of the exhalation cycle. This point 175 a or other informationderived from the sensed signal (FIG. 16E) may be used to triggerstimulation in accordance with one or more stimulation protocols of theembodiments of the invention described herein.

The information ascertained from the sensed signals may be used todetermine triggers for providing stimulation. Examples of such triggersare described with reference to the various stimulation protocols andtechniques described in the various embodiments herein.

FIG. 16B illustrates two sequential integrated waveforms of exemplaryintegrated signals corresponding to two serial respiratory cycles. Aninspiration portion 172 may be observed using an EMG, flow or tidalvolume correlated signal. An exhalation period 176 may be observed usinga flow or tidal volume correlated signal. The waveform 170 has abaseline 170 b, inspiration cycle 171, a measured inspiration cycle 172,a point of 10% of peak inspiration 173 (comp 1), a point of 90% of peakof inspiration 174 (comp 2), a peak 175 where inspiration ends andexhalation begins, and exhalation cycle 176 a fast exhalation portion177 of the exhalation cycle 176, a 90% of peak exhalation point 178(comp 3), a 10% of peak exhalation point 179 (comp 4), an actualrespiratory cycle 180 and a measured respiratory cycle 181. 50% ofexhalation (comp 5) may be used to trigger stimulation of thehypoglossal nerve to open the upper airway. The second waveform 182 issimilarly shaped. The 10% inspiration 183 of the second waveform 182marks the end of the measured respiratory cycle 181, while the 10% point173 of the waveform 170 marks the beginning of the measured respiratorycycle 181.

FIG. 16C illustrates a schematic EMG envelope corresponding to aninspiration portion e.g., 172 of a respiration cycle. FIG. 16Dillustrates a schematic flow correlated signal corresponding to arespiration cycle.

The upper airway pressure sensed with sensor 56 provides a signalcorrelated to the inverse of flow. The inverse of the upper airwaysignal may be processed as a flow correlated signal as set forth hereinto provide respiration information.

Intrapleural pressure may be sensed with sensor 57 to provide a signalas schematically set forth in FIG. 16E. This may processed similar to anintegrated flow (or Tidal Volume signal) as described herein to provideexhalation cycle information or lung volume information. Exhalationcycle information or lung volume information may be used as a triggerfor stimulation as set forth herein.

In FIG. 3 a circuit for an external device 140 is illustrated. Theexternal device 140 comprises a processor 145 for controlling theoperations of the external device. The processor 145 and otherelectrical components of the external device 140 are coordinated by aninternal clock 150 and a power source 151. The processor 145 is coupledto a telemetry circuit 146 that includes a telemetry coil 147, areceiver circuit 148 for receiving and processing a telemetry signalthat is converted to a digital signal and communicated to the processor145, and a transmitter circuit 149 for processing and delivering asignal from the processor 145 to the telemetry coil 146. The telemetrycoil 147 is an RF coil or alternatively may be a magnetic coil dependingon what type of coil the telemetry coil 107 of the implanted controlunit 100 is. The telemetry circuit 146 is configured to transmit signalsto the implanted control unit 100 containing, e.g., programming or otherinstructions or information, programmed stimulation protocols, rates andpulse widths, electrode configurations, and other device performancedetails. The telemetry circuit 146 is also configured to receivetelemetry signals from the control unit 100 that may contain, e.g.,sensed and/or accumulated data such as sensed information correspondingto physiological parameters, (e.g., sensed EMG activity, sensed nerveactivity, sensed responses to stimulation, sensed position information,sensed flow, or sensed movement information). The sensed physiologicalinformation may be stored in RAM event memory 158 or may be uploaded andthrough an external port 153 to a computer, or processor, eitherdirectly or through a phone line or other communication device that maybe coupled to the processor 145 through the external port 153. Theexternal device 140 also includes ROM memory 157 for storing andproviding operating instructions to the external device 140 andprocessor 145. The external device also includes RAM event memory 158for storing uploaded event information such as sensed information anddata from the control unit, and RAM program memory 159 for systemoperations and future upgrades. The external device also includes abuffer 154 coupled to or that can be coupled through a port to auser-operated device 155 such as a keypad input or other operationdevices. Finally, the external device 140 includes a display device 156(or a port where such device can be connected), e.g., for displayvisual, audible or tactile information, alarms or pages.

The external device 140 may take or operate in, one of several forms,e.g. for patient use, compliance or monitoring; and for health careprovider use, monitoring, diagnostic or treatment modification purposes.The information may be downloaded and analyzed by a patient home unitdevice such as a wearable unit like a pager, wristwatch or palm sizedcomputer. The downloaded information may present lifestyle modification,or compliance feedback. It may also alert the patient when the healthcare provider should be contacted, for example if there ismalfunctioning of the device or worsening of the patient's condition.

Other devices and methods for communicating information and/or poweringstimulation electrodes as are know in the art may be used as well, forexample a transcutaneously inductively coupled device may be used topower an implanted device.

According to one aspect of the invention, the stimulator operates tostimulate and/or manipulate breathing to mitigate (i.e., avoid or reduceeffects of) an obstructive respiratory event by stimulating the phrenicnerve, diaphragm or associated tissue according to one or moreprotocols, to elicit a respiratory response. Examples of suchstimulation protocols are described herein with reference to FIGS.4A-23D. In accordance with another aspect of the invention, suchstimulation is provided prior to the onset of an obstructive respiratoryevent or prior to airway obstruction to prevent an obstructiverespiratory event from occurring or the airway from fully closing. Inaccordance with another aspect of the invention, stimulation is providedat a low level following obstructive sleep apnea or effective airwayclosure.

In accordance with one aspect of the invention as described with respectto FIGS. 4A-4D, 5A-5C, 7A-7B, 8A-8B, 9A-9C, 10A-10C and 12A-12B,stimulation of the phrenic nerve or diaphragm is provided to increasefunctional residual capacity, i.e., end expiratory volume, at leastuntil onset of a subsequent respiration cycle. In accordance with theinvention, an increased functional residual capacity is believed toassist in maintaining an airway passage open to a sufficient degree toprevent or reduce airway collapse that results in an obstructiverespiratory event.

In accordance with another aspect of the invention, as described withrespect to FIGS. 4A-4D, 5A-5B, 6A-6B, 10A-10C, 11A-11B, 12A-12B or14A-14B, stimulation of the phrenic nerve or diaphragm is provided toincrease tidal volume sufficiently to increase upper airway patency. Itis believed that increasing the tidal volume may contribute tostiffening the upper airway. Preferably the same or a lower peak flowwith respect to intrinsic flow is provided to avoid an increase innegative pressure applied to the upper airway that would decrease upperairway patency. Therapy may be delivered to increase flow in the casewhere flow is below normal. In cases where flow is normal, or limited byobstruction, tidal volume may be increased through extension of theinspiration duration. An upper airway hysteresis effect may also occurwhere the volume of a breath is increased above a normal tidal volumeand the stiffening of the upper airway during inspiration does notreturn entirely to a relaxed resting state. It is accordinglyadditionally believed that an upper airway hysteresis effect wouldstiffen the upper air passageway for subsequent breaths and will therebyprevent or mitigate airway narrowing or collapse that results inobstructive sleep apnea.

In accordance with one aspect of the invention, as described withrespect to FIGS. 9A-9C, 11A-11B, 13A-13B and 14A-14B, stimulation isprovided to create ventilatory stability and to thereby reducefluctuations in the upper airway passage muscles that may lead to upperairway collapse where ventilatory drive is low or unstable. “Ventilatoryinstability is defined herein to mean varying breathing rate and/ortidal volume outside of normal variations.” Ventilatory stabilityassociated with obstructive respiratory events, as opposed to periodicbreathing or Cheynes-Stokes respiration, include, for example,variations in breathing rate and/or tidal volume associated with sleeponset, change in sleep state, and REM sleep.

In accordance with another aspect of the invention, as described withrespect to FIGS. 4A-4D, 6A-6C, 9A-9C and 10A-10C, 11A-11B, 12A-12B, and14A-14B, stimulation of the phrenic nerve or diaphragm is providedduring intrinsic breathing during or at the end of an intrinsicinspiration portion of a breathing cycle. For purposes of the inventionherein, the intrinsic cycle may be detected near onset of inspiration.Other portions of a breathing cycle may be identified for breathingstimulation. Alternatively, the beginning of the breathing cycle or aportion of the breathing cycle may be predicted, e.g., based on atypical breathing pattern of an individual patient.

A stimulation signal may be provided during inspiration of intrinsicbreathing for various purposes. In accordance with a variation of theinvention, stimulation is provided during intrinsic inspiration toprovide initial and more gradual control of breathing according to aprotocol. Then, breathing control protocols may be applied so thatairway closure due to stimulation is avoided. Tidal volume is increasedgradually so as to balance out an increase in upper airway resistancethat can occur with stimulation during intrinsic inspiration.Stimulation of breathing during intrinsic inspiration in accordance withvariations of the invention is configured to contribute to creating theeffect of increasing functional residual capacity. In some variations ofthe invention, stimulation during intrinsic breathing is configured tostiffen the upper airway, thereby increasing upper airway patency.Stimulating during inspiration in accordance with a protocol of theinvention may also increase upper airway hysteresis. In one embodiment,breathing is stimulated at least in part during intrinsic inspiration sothat the resulting tidal volume is greater than intrinsic normal volume,while peak flow is maintained near normal peak flow to avoid upperairway closure. Stimulating during intrinsic inspiration may also beused to normalize breathing in an obstructive sleep apnea patient and toincrease ventilatory stability associated with airway obstructions.Stimulating at least in part during intrinsic inspiration may increaseinspiration duration which may allow increase of tidal volume withoutsignificantly increasing the peak flow. (Increasing peak flow mayincrease the possibility of airway closure.) According to oneembodiment, peak flow is provided at, near or below intrinsic peak flow.

While stimulating breathing during intrinsic inspiration is describedherein in use with a device and method of treating obstructive sleepapnea, other breathing or related disorders may be treated bystimulating breathing during intrinsic inspiration in accordance withanother aspect of the invention.

In accordance with another aspect of the invention and as illustrated inFIGS. 4A-4D, and 5A-5C the phrenic nerve or diaphragm is stimulated toprovide deep inspiration therapy to a subject. Deep inspiration therapyinvolves stimulating a breath that is of a greater tidal volume than anormal breath. According to a preferred embodiment, deep inspirationstimulation provides a breath having a greater inspiration duration thanthat of a normal breath. Rather than substantially increasing peak flowor rather than increasing the magnitude of diaphragm contraction, theincrease in inspiration duration to increase tidal volume is believed toreduce the likelihood of airway closure with stimulation. Deepinspiration stimulation may be provided intermittently throughout thenight or a portion of the night while a patient sleeps, thus preventingan obstructive respiratory event. While deep inspiration therapy isdescribed herein in use with a device and method of treating obstructivesleep apnea, other breathing or related disorders may be treated by deepinspiration therapy.

In accordance with another aspect of the invention as described withrespect to FIGS. 6A-6B, 7A-7B, 8A-8B, 9A-9C, 10A-10C and 12A-12B, theexhalation cycle is manipulated to provide a therapeutic effect.According to one aspect of the invention, increased functional residualcapacity is provided by manipulating the exhalation phase. Manipulationof the exhalation phase may be provided using stimulation during theexhalation phase. The exhalation phase may also otherwise be manipulatedin length or duration.

In accordance with another aspect of the invention as described withrespect to FIGS. 7A-7B 8A-8B, 9A-9C, and 10A-10C, a low levelstimulation is applied during all or a portion of the respiration cycle.Among other therapeutic effects such stimulation may increase functionalresidual capacity. Such low level stimulation may be directed to providean increased tidal volume during a rest phase of a respiration cycle bysustaining a low level contraction of the diaphragm. Typically such lowlevel stimulation would be lower than the relative threshold foreliciting breathing. This level may vary from patient to patient and maybe determined on an individual basis. It may also depend on electrodetype and placement. Typically the stimulation is lower than 8 mA.

In accordance with another aspect of the invention, as described withrespect to FIGS. 9A-9C, 12A-12B, 13A-13B, and 14A-14B, stimulation ofthe phrenic nerve or diaphragm is provided to control breathing.According to one aspect of the invention, breathing is controlled eitherby inhibiting respiratory drive, entraining breathing or othermechanisms. Controlling breathing according to one variation comprisesstimulating to control or manipulate the central respiratory drive.Controlling breathing may include taking over breathing to control oneor more parameters of a stimulated breath. Entraining breathing mayinclude stimulating at a rate greater than but close to, or equal to theintrinsic respiratory rate until the central pattern generator activatesthe respiration mechanisms, which includes those of the upper airway, inphase with the stimulation. As an alternative or in addition,inspiration duration may be increased with respect to the totalrespiration cycle or exhalation. While controlling breathing isdescribed herein in use with a device and method of treating obstructivesleep apnea, other breathing or related disorders may be treated bycontrolling breathing in accordance with another aspect of theinvention.

According to another aspect of the invention stimulation is used toprovide ventilatory stability. Examples of providing ventilatorystability are shown in FIGS. 9A-9C, 10A-10B, 11A-11B, 13A-13B and14A-14B. Ventilatory stability may be provided by stimulating breathingto increase a falling tidal volume towards that of a normal breath.Ventilatory stability may also be provided by controlling breathing in amanner that creates stability. Ventilatory stability may also beprovided by entraining breathing. Instability in ventilatory rate thatindicates the onset of obstructive sleep apnea may be treated bycontrolling breathing for a preset period of time as described withrespect to FIGS. 9A-9B, 13A-13B or FIGS. 14A-14B. Instability inventilatory rate may also be treated by normalizing tidal volume usingstimulation as described with respect to FIGS. 10A-10B or 11A-11B.

Referring to FIGS. 4A-4D, stimulation and respiration waveformsillustrating a method using a device in accordance with one aspect ofthe invention are illustrated. A device and method creates increasedfunctional residual capacity and upper airway patency by providing deepinspiration. In this particular embodiment, deep inspiration is providedby stimulating during a portion of an inspiration cycle. Stimulation mayextend beyond the duration of an intrinsic breath. The stimulation isprovided to increase tidal volume by extending the duration of theinspiration cycle. (While preferably maintaining peak flow at or nearintrinsic peak flow, i.e. normalizing flow.) In accordance with aprotocol, stimulation through one or more electrodes associated with thediaphragm or phrenic nerve is provided to cause the diaphragm tocontract to cause a deep inspiration breath. Stimulation may be providedwhen a characteristic preceding an obstructive respiratory event isdetected. For example, if erratic breathing occurs or if the tidalvolume drops below a given threshold level, then stimulation isprovided. The resulting breath comprises a deep inhalation breath (i.e.,a greater tidal volume than a normal, intrinsic breath.) A deepinspiration breath may then be repeated periodically to prevent furtherdrop in tidal volume by increasing the functional residual capacity andcreating upper airway stiffening. The device may also be programmed torepeat the deep breath a given number of times before ceasing thestimulation.

One possible characteristic of breathing in obstructive sleep apneapatients is a decreasing tidal volume. The ultimate closure of an airpassageway in an obstructive sleep apnea event thus may be preceded by agradual decrease in ventilatory volume. Another possible characteristicof breathing in obstructive sleep apnea patients is an erratic breathingpattern. In a patient who is diagnosed with obstructive sleep apnea,respiration may be monitored using EMG or other sensors that senserespiration parameters corresponding to tidal volume or flow (forexample, diaphragm movement which corresponds to airflow may be sensed;impedance plethysmography may be used; or flow itself may be sensedusing a sensor implanted in the trachea.) FIGS. 16A-16D illustratemonitoring or detection of various aspects or parameters of respirationon a breath by breath basis. Tidal volume is monitored and a decrease intidal volume characteristic (FIG. 4A) or an erratic breathing pattern(FIG. 4B) in an obstructive sleep apnea patient is detected. (Monitoredtidal volume as used herein may also include a monitored tidal volumecorrelated signal). Estimated minute ventilation (i.e., determined bymultiplying respiratory rate times volume of a breath) may also be usedto determine the impending onset of an obstructive respiratory event.

For purposes of detecting a threshold volume on a breath-by-breath basisor in real time, a programmed threshold may be set. The threshold valuemay be determined when initializing the device as the value at or belowwhich preventative or mitigating treatment is required or is otherwiseoptimal. This value may be programmed into the device. A minimum safetythreshold value may also be established below which stimulation isinhibited to prevent airway closure. As such, the minimum safetythreshold may be set as a value sufficiently above a tidal volume wherestimulation treatment if provided would further close an air passageway.

When monitoring tidal volume, the area under the inspiration flow curveor EMG envelope of an individual breath may be monitored to determinetidal volume of a breath. The tidal volume is compared to a thresholdvalue for a particular patient. Other parameters may be used to identifywhen tidal volume has dropped below a predetermined threshold, forexample baseline tidal volume rate variance over a period of time may bemonitored and compared to a normal variance. The normal variance may bedetermined on a patient-by-patient basis and programmed into the device.

FIG. 4A illustrates a breathing pattern where a decrease in tidal volumeultimately ends in an obstructive sleep apnea event. Accordingly, tidalvolume of intrinsic breaths 411-415 of an obstructive sleep apneapatient is shown in FIG. 4A. The tidal volume of breaths 411-415gradually decreases until the airway narrows ultimately leading to anairway obstruction. An obstructive respiratory event occurs with totalairway closure after breath 415. An obstructive respiratory event mayalso be an airway narrowing, e.g., hypopnea. An obstructive respiratoryevent may be detected by monitoring a decrease in tidal volume, forexample as a predetermined percentage of normal or intrinsic tidalvolume. The threshold 450 below which treatment is to be provided by thedevice is shown in FIGS. 4A-4D. FIG. 4D illustrates a stimulationprotocol corresponding to the resulting tidal volume waveforms of FIG.4C.

FIG. 4C illustrates tidal volume of a patient treated using a deepinspiration stimulator. The stimulator detects the drop in tidal volume(breath 413) below a threshold level as described above with respect toFIGS. 4A-4B. During the subsequent breath 414, stimulation 434(schematically illustrated as an envelope of a burst of pulses) isprovided by the stimulator to provide a deep inspiration breath 424 withthe breath 414. The deep inspiration breath 424 comprises a breath thathas a tidal volume greater than the tidal volume of a normal orintrinsic breath. After one or more deep inspiration breathstimulations, the tidal volume is expected to return to normal or closeto normal, e.g. at breaths 425-429. Synchronization is provided wherebythe onset of inspiration is detected and stimulation is provided duringthe breath. According to one variation, a tidal volume that is greaterthan or equal to a predetermined percentage of a normal inspiration isdetected (e.g. 10% of tidal volume as described with respect to FIGS.16A-16E). Then when the onset of the next inspiration is detected,stimulation is provided. Additional periodic delivery of deepinspiration paced breaths may be provided synchronously orasynchronously with the intrinsic breathing, to prevent or mitigatedrops in tidal volume. In accordance with this aspect of the invention,as illustrated in FIG. 4D an additional pacing pulse or burst of pulses439 is provided to stimulate deep inspiration breath 419. Thus, thetherapy described with reference to FIG. 4D may prevent a further dropin tidal volume, thereby reducing the occurrence of obstructiverespiratory events or other breathing related disorders.

FIGS. 5A-5C illustrate use of a deep inspiration stimulator inaccordance with the invention. FIG. 5A illustrates a breathing patternwhere a decrease in tidal volume ultimately ends in an obstructiverespiratory event. Accordingly, tidal volume of intrinsic breaths511-515 of an obstructive sleep apnea patient is shown in FIG. 5A withthe airway ultimately closing after breath 515. In FIG. 5A, no treatmentis provided. Other pre-obstructive breathing characteristics may also beused to determine when an OSA event is likely to be imminent.

A threshold 550 below which treatment is to be provided by the device isshown in FIGS. 5A and 5B. This threshold may be determined in a mannersimilar to that described with respect to FIGS. 4A-4C. FIG. 5Cillustrates a stimulation protocol corresponding to the resulting tidalvolume waveforms of FIG. 5B. FIG. 5B illustrates the tidal volume of apatient treated using a deep inspiration stimulator who would otherwisehave had a breathing pattern shown in FIG. 5A. The stimulator detectsthe drop in tidal volume (breath 513) below a threshold level 550 in amanner similar to that described above with respect to FIGS. 4A-4D.Prior to what would have been the subsequent breath 514, i.e., at somepoint during the intrinsic exhalation period or rest period, thestimulator provides stimulation 533 to elicit a deep inspiration breath523 (FIG. 5B). The deep inspiration breath 523 comprises a breath with atidal volume greater than the tidal volume of an intrinsic or normalbreath. Preferably, the peak flow remains relatively normal whileinspiration duration increases thus increasing tidal volume. After oneor more deep inspiration breath stimulations, the tidal volume returnsto normal, e.g., at breaths 524-525. At breaths 526, 527 a slightdecrease in respiratory drive is shown with a decreased tidal volume.Periodic delivery of deep inspiration breaths may be provided to preventor mitigate drops in tidal volume. In accordance with this aspect of theinvention, as illustrated in FIG. 5C an additional pacing pulse or burstof pulses 538 is provided prior to the onset of the next intrinsicbreath to stimulate deep inspiration breath 528 which is then followedby a normal breath 529. The deep inspiration breaths 523 or 528 areintended to increase the functional residual capacity of the lung and/orenhance upper airway patency. Thus, the therapy may prevent further dropin tidal volume, thereby reducing the incidence of obstructive sleepapnea or other breathing related disorders.

FIGS. 6A-6B illustrate stimulation and inspiration waveformscorresponding to a variation of stimulation device and method of theinvention. The stimulation protocol of FIGS. 6A-6B provides stimulationat the end of an inspiration cycle increasing inspiration duration,thereby increasing tidal volume. A resulting normalized peak flow andincreased tidal volume is believed to stiffen or lengthen the upperairway and may create an upper airway hysteresis effect. Increased tidalvolume may provide more time and volume for gas exchange. Among othereffects, normalized peak flow and increased tidal volume are believed toprevent airway collapse attributable to obstructive sleep apnea.

FIG. 6A illustrates normal inspiration duration 610 of an intrinsicbreath and increased inspiration duration 620 that would result fromstimulation 650 shown in FIG. 6B. Stimulation 650 is provided at the endof an inspiration period for a predetermined amount of time T₆ tomaintain flow and prolong inspiration for the additional period of timeT₆. The end of the inspiration period may be determined in a manner asdescribed with reference to FIGS. 16A-16D herein. The time T₆ may beselected and/or programmed into the device. The time may be determinedto elicit a desired response. A short stimulation period, for example,as short as 0.1 seconds may be used.

FIGS. 7A-7B illustrate stimulation and inspiration waveformscorresponding to a variation of a stimulation device and method of theinvention. The stimulation protocol of FIGS. 7A-7B provides low levelstimulation at the beginning or the end of an exhalation portion of arespiration cycle, or at some time within the exhalation portion of therespiration cycle. This is believed to preserve lung volume prior to thenext inspiration. The manipulation of the exhalation cycle is thusbelieved to increase functional residual capacity. FIG. 7A illustratestidal volume 730 that would result from stimulation 750 shown in FIG.7B. Stimulation 750 is provided at an end portion of an exhalation cycleto preserve some volume 740 for the next inspiration cycle thusincreasing the functional residual capacity. The end of the exhalationcycle may be determined by determining the end of inspiration and thenbased on a known respiration rate, estimating the time of the end of theexhalation cycle. Alternatively, flow correlated respiration parametersmay be sensed and the desired portion of the exhalation cycle may bedetermined. FIGS. 16A-16D illustrate manners for determining portions ofa respiration cycle.

FIGS. 8A-8B illustrate stimulation and inspiration waveformscorresponding to a variation of a stimulation device and method or theinvention. The stimulation protocol of FIG. 8B provides a low level of acontinuous stimulation to cause the diaphragm to remain slightlycontracted, thereby increasing functional residual capacity. FIG. 8Billustrates stimulation provided while FIG. 8A illustrates tidal volume.As shown, the tidal volume is elevated during the end portion of theexhalation cycle 840 (FIG. 8A) relative to end expiratory tidal volumebefore the stimulation.

FIGS. 9A-9C illustrate stimulation and inspiration waveformscorresponding to a variation of a stimulation device and method of theinvention. The stimulation protocol provides a combination of therapiesor protocols including increasing functional residual capacity andcontrolling breathing. The stimulation protocols manipulate exhalationand control breathing. The stimulation protocol of FIGS. 9A-9C providesa low current stimulation 950 as shown in FIG. 9C during the exhalationphase of a respiration cycle and a stimulated breath 951 delivered atthe end of exhalation. The stimulated breath 951 is provided at a higherrate R2 than the intrinsic rate R1. The stimulation 950 is appliedbetween the end of inspiration cycles 920, 921, 922 and the onset of thenext inspiration cycles, 921, 922, 923 respectively to increasefunctional residual capacity. Stimulation 951 produces inspirationcycles 920, 921, 922, 923. Flow waveforms 930, 931, 932, 933respectively of respiration cycles 920, 921, 922, 923 are shown in FIG.9A. Tidal volume waveforms 940, 941, 942, 943 respectively ofrespiration cycles 920, 921, 922, 923 are shown in FIG. 9B.

FIGS. 10A-10B illustrate stimulation and inspiration waveformscorresponding to a variation of a stimulation device and method of theinvention. Stimulation is provided during the inspiration cycle in amanner shown in FIGS. 7A-7B to increase inspiration duration and tidalvolume (with normalized peak flow) in order to stiffen the upper airway.Also, a low level stimulation is provided to increase lung capacity atthe end of inspiration and until the beginning of the next inspirationcycle to increase the functional residual capacity. A first intrinsicrespiration cycle 1020 is illustrated. At the onset of exhalation 1021of the respiration cycle 1020, a low level stimulation 1050 is applieduntil the onset of the inspiration cycle of the next respiration cycle1022. At the detection of the onset of the next respiration cycle 1022(as described in FIGS. 16A-16E), stimulation 1055 is provided. Thestimulation 1055 is applied at least in part during the inspirationcycle 1022. The corresponding tidal volumes 1040, 1042 of respirationcycles 1020, 1022 respectively are illustrated in FIG. 10A. Thecorresponding flows 1030, 1032 of respiration cycles 1020, 1022respectively are shown in FIG. 10B.

Referring to FIGS. 11A and 11B, stimulation and inspiration waveformsillustrate a stimulation device and method of the invention. Stimulationis provided in a manner similar to that described with reference toFIGS. 4A-4D. In accordance with FIGS. 11A and 11B, stimulation isprovided to prevent or mitigate obstructive sleep apnea by stabilizingthe tidal volume. FIG. 11A schematically shows the tidal volume assensed by EMG sensors and illustrates the intrinsic breathing 1111-1117of a subject, as well as the resulting breathing 1124, 1125. FIG. 11Billustrates the stimulation pulse envelopes 1160 of stimulation appliedto the diaphragm or phrenic nerve of a subject in accordance with oneaspect of the invention. Referring to FIG. 11A, the tidal volume fromintrinsic breathing gradually decreases (1111, 1112) until it fallsbelow a threshold level 1150 (1113-1115) and then resumes normal tidalvolume (1116-1117) after treatment. After breath 1113 is detected belowthreshold level 1150, a stimulation pulse 1160 is provided during and insynchronization with the subsequent breath 1114, 1115 to thereby providethe resulting breath. The resulting breaths have waveforms 1124, 1125with tidal volumes increased to a level of normal breathing. Accordingto one variation, stimulation is provided with the goal of stabilizingor normalizing breathing. After stimulating for a given period of timeor number of breaths, breathing is monitored to determine if it isnormalized (for example with breaths 1116, 1117) at which time thestimulation may be discontinued.

FIGS. 12A-12B illustrate stimulation and inspiration waveformscorresponding to a variation of a stimulation device and method of theinvention. The stimulation protocol of FIGS. 12A-12B provides a longrising stimulation during at least the inspiration portion of arespiration cycle to increase inspiration time of the cycle with respectto expiration time(or total percentage of the cycle that corresponds toinspiration). Using breathing control therapy to lengthen theinspiratory duration, expiratory time is reduced and the baselinerelaxation lung volume is not completely restored, leading to anincreased functional residual capacity. The stimulation protocol therebymanipulates or shortens the length of the exhalation portion of therespiration cycle. In addition, the respiration rate is increased toshorten the exhalation portion of the respiration waveform. Thus, theprotocol is directed to increasing the functional residual capacity ofthe lungs by manipulating the expiration phase of the respiration cycle.

FIG. 12A illustrates flow and FIG. 12B illustrates correspondingstimulation. Referring to FIG. 12A a first intrinsic breath 1210 isshown with an intrinsic inspiration volume V_(II) and an intrinsicexpiration volume V_(IE). Prior to time T_(12A), breathing may beentrained (for example, as described with respect to FIGS. 13A and 13Bherein) at a rate slightly faster than the intrinsic rate but atapproximately a normal tidal volume and waveform 1210. Thereafter,stimulation 1240 is applied during a rest period (i.e. at an end portionof the exhalation phase) of a respiration cycle 1220 following breath1210. The stimulation is provided using a long rising pacing pulse sothat the respiration cycle is lengthened by a time T_(12B) to preventfull expiration before the next inspiration cycle of the next breath1230 which is provided by stimulation 1250. Stimulation 1250 is providedat a rate slightly faster than the previous stimulation 1240. Thus,exhalation is shortened, preventing exhalation portion 1260, and thusincreasing the functional residual capacity of the lungs.

Referring to FIGS. 13A-13B, stimulation and respiration waveformsillustrating a stimulation method using a stimulation device inaccordance with one aspect of the invention are illustrated. Accordingto FIGS. 13A-13B, breathing is stabilized by stimulating to control ormanipulate breathing. FIGS. 13A-13B illustrate a variation of atechnique for controlling breathing.

FIG. 13A illustrates the flow of air representing respiration waveformsover time. Breathing control may be used for a number of differentpurposes. It may be done with or without sensing a condition thatindicates a respiratory disturbance is present or occurring. It may bedone for a predetermined period of time or during certain times of dayor during certain sleep cycles. It may be done to stabilize breathing.

For example, if tidal volume falls below a predetermined threshold,stimulation may begin. Stimulation may also be provided periodically orat times of greater vulnerability to obstructive sleep apnea or otherdisorders associated with breathing disorders. FIG. 13B illustratesenvelopes 1340 of stimulation pulses provided to control breathingduring the course of stimulation. FIG. 13A illustrates the breaths 1360resulting from the stimulation illustrated in FIG. 13B.

According to this embodiment, the stimulator first takes over breathingby providing stimulation 1340 (as illustrated in FIG. 13B) at a timeduring an end portion 1320 of the exhalation phase of an intrinsicrespiration cycle, prior to the onset of the next respiration cycle (Asillustrated in FIG. 13A). The stimulation 1340 is provided at a rategreater than the intrinsic rate, i.e., where the cycle length T1 is lessthan the intrinsic cycle length T1+x. As illustrated the duration of theintrinsic respiration cycle is T₁+x. The duration of the respirationcycles of the stimulated breathing begins at T₁ to take over breathing.After a period of time of taking over breathing, the respiration cyclelength is then gradually increased to T1+m, t1+n, and T1+o where m<n<o<xand where o approaches x in value. Breathing is thereby controlled andventilation is accordingly stabilized.

According to one aspect of the invention, breathing is believed to becontrolled by stimulating for a period of time at a rate greater thanbut close to the intrinsic respiratory rate. Breathing may be controlledthrough inhibition of the central respiratory drive or entrainment. Inorder to entrain breathing, stimulation may be provided until thecentral pattern generator activates the respiration mechanisms, whichincludes those of the upper airway, in phase with the stimulationthrough various feedback mechanisms. It is believed that breathing maybe entrained when the central respiratory drive is conditioned to adaptto stimulation. When breathing is entrained, it may be possible tofurther slow respiration rate or the respiration cycle length so that itis longer than the intrinsic length 1320.

Some methods for controlling breathing are described for example in U.S.application Ser. No. 10/966,474, filed Oct. 15, 2004 and incorporatedherein by reference.

Referring to FIGS. 14A and 14B inspiration flow waveforms andstimulation pulse envelope waveforms are shown corresponding to avariation of a stimulation device and method of the invention. Inaccordance with this variation, the stimulation device stimulates duringintrinsic breaths 1411, 1412, 1413 to provide resulting breaths 1421,1422, 1423. The intrinsic breaths occur at a rate B1 as illustrated inFIG. 14A. The first stimulation 1451 is applied at a delay D1 from theonset of intrinsic breath 1411. The next stimulation 1452 is provided ata delay D2 from the onset of intrinsic breath 1412 and the subsequentstimulation pulse 1453 is provided at a delay D3 from the onset ofintrinsic breath 1413. The time between the first and second stimulation1451 and 1452 is T_(1+Δ) a while the time between the second and thirdstimulation 1452 and 1453 is T₁, i.e., shorter. Thus stimulation isprovided gradually closer and closer to the onset of stimulation togently take over breathing with stimulation at least in part duringintrinsic inspiration. The stimulation 1453 is essentially synchronouswith the start of the intrinsic inspiration 1413, to create theresulting breath 1423. Stimulation may be delivered at this rate for aperiod of time. Then the next stimulus 1454 is delivered at a ratefaster than normal at a respiration cycle length timed to thereby elicitpaced breath 1424. The next stimulus 1455 is delivered at the intervalT2, to induce another paced breath 1425, and this may be continued forsome time in order to control breathing. This may lead to theentrainment of the central respiratory control system. Also, rate may beincreased gradually until no intrinsic breaths occur between the pacedbreaths. When control of respiratory rate is achieved (and possiblyentrainment), if a slowing of the breathing rate is desired, the pacingrate can be decreased gradually as shown schematically in the Figure bystimuli delivered at a cycle length of T2+x, followed by T2+2x, inducingpaced breaths 1426 and 1427. It is believed that if entrained, ifdesired, the stimulation rate may bring the respiration rate slower thanthe intrinsic rate and tidal volume may be manipulated. After a periodof time or after breathing has been controlled as desired, the intrinsicbreathing may be allowed to resume, for example, as shown with breath1418. The patient may be weaned off stimulation, for example, asdescribed herein.

In accordance with another aspect of the invention, the phrenic nerve ordiaphragm may be stimulated using the low level stimulation as describedherein, through an OSA event after obstructive sleep apnea event hasoccurred

The stimulation described or shown herein may be comprised of severalstimulation parameters. For example a burst of pulses may form a squarepulse envelope or may ramp up or down in amplitude or a combinationthereof. The frequencies may vary or may be varied depending upon adesired result. In accordance with one embodiment, the burst frequencyranges between 5-500 Hz and more preferably between 20-50 Hz. However,other frequency ranges may be used as desired. Low level pulses orcontinuous stimulation may comprise stimulation at about 8 mA or less ormay be determined on a case-by-case basis. However, other amplitudes andfrequencies may be used as desired. The stimulation may be monophasic ormay be biphasic. Stimulation may be provided in response to sensingrespiration or other parameters. Alternatively, stimulation may beprovided periodically or during specific times, for example duringsleep, during sleep stage transitions, or during non-REM sleep.

Stimulation may also be slowly phased out. That is the patients may beweaned from stimulation slowly. In general, when paced breathing isongoing, and the therapy is to be stopped, it may be beneficial to weanthe patient off the therapy to avoid creating apnea that may lead toobstructions or arousals. Weaning off would involve a gradual decreasein rate, until an intrinsic breath is detected. Once an intrinsic breathis detected, the device would discontinue pacing and would return tomonitoring mode. An example of a protocol for weaning a patient off fromstimulation is described, for example, in U.S. application Ser. No.10/686,891 filed Oct. 15, 2003. Other variations of weaning patients offare also possible.

FIG. 15 is a flow chart illustrating operation of a system or device inaccordance with the invention. An implanted device is initialized duringan initialization period 1510. During the initialization period, amongother things, the thresholds may be set up for triggering or inhibitingtherapy. The thresholds may be set up by observing patient breathingover time. Therapy modalities may also be chosen, for example by testingvarious stimulation protocols to optimize therapy. For example,information obtained from one or more breaths can be used to set pacingparameters for subsequent therapies. Examples of data that can beobtained from one or a series of breaths include: rate, tidal volume,inspiration duration, flow parameters, peak flow, and/or duty-cycle. Inthe case of paced breathing therapies or breathing control (and possibleentrainment), the rate of intrinsic breathing could be measured, andthen paced breathing could be delivered, for example, at a faster ratethan the measured rate. As another example, one could measure theinspiration duration of previous intrinsic breaths, and induce a breathto create an inspiration duration longer (or shorter) than the previousintrinsic breaths. During initialization or when updating the device,test stimulation signals and measured responses may be used to determineappropriate stimulation parameters.

During operation, the therapy is turned on 1520. This may be doneautomatically or manually. Therapy is delivered 1530 as is determined tobe appropriate for a particular patient in accordance with one or moreprotocols, for example as described herein.

Referring to FIGS. 17A-17E combination diaphragm/phrenic nerve and upperairway stimulation and respiration related waveforms illustrate astimulation device and method in accordance with the invention. A lowlevel continuous stimulation 1750 is applied (FIG. 17D) to the diaphragmor phrenic nerve in a manner similar to that described with reference toFIGS. 8A and 8B. The low level or volume bias stimulation may beprovided for a predetermined period of time or on-demand, based onsensed information, for example, that indicates a greater likelihood ofa respiratory disorder event occurring, for example by identifying abreathing pattern prior to onset of OSA or other disorder, or byidentifying a flow limitation from an EMG.

FIG. 17E illustrates a stimulation signal 1760 applied to thehypoglossal nerve or upper airway. In accordance with the invention, itis believed that a combined effect of providing a volume biasstimulation and stimulating the upper airway or hypoglossal nerveprovides improved upper airway tonicity and/or patency. Also, inaccordance with the invention, the upper airway is preactivated prior tothe contraction of the diaphragm. Accordingly, the airway may beprepared for negative pressure caused by diaphragm contraction which mayhave a collapsing effect on the upper airway.

Stimulation of the hypoglossal nerve (or upper airway) as illustrated inFIG. 17E may be triggered a number of ways. FIG. 17A illustrates thesensed EMG envelope 1720 corresponding to a subject stimulated inaccordance with FIGS. 17D and 17E. The EMG signal 1720 may be processedto identify the end 1725 of an EMG envelope corresponding to a firstbreath 1730. The end 1725 of the EMG envelope of the first breath 1730may be used to trigger hypoglossal nerve stimulation 1770 prior to asecond breath 1735. The system may be programmed to wait a predeterminedamount of time 1765 following the detected end 1725 of the EMG envelopeof the first breath 1730 to stimulate the hypoglossal nerve. The system,for example may wait a percentage of an intrinsic exhalation period.This intrinsic exhalation period may be determined a number of ways. Forexample, the duration of an intrinsic inspiration period may besubtracted from the duration of an intrinsic respiration cycle.Alternatively, an intrinsic exhalation period may be determined bymeasuring the duration of one or more intrinsic expiration cycles usinga flow correlated signal.

FIG. 17B illustrates an upper airway pressure waveform 1740 that may besensed (or an other flow correlated signal), for example using sensor 86positioned in the mouth (epiglossal). The sensed pressure corresponds tothe breathing of the subject as indicated by the EMG envelope 1710 ofFIG. 17A. The upper airway pressure waveform 1740 may be used to triggerhypoglossal nerve stimulation. The peak negative pressure trigger point1747 may be detected by analyzing the waveform 1740 as described withrespect to FIGS. 16A-16E. The peak negative pressure 1741 occurs at atime during exhalation that generally corresponds to 50% of exhalation(see comp 5, FIG. 16B). Similarly, tidal volume or intrapleural pressure(generally correlated with inverse of tidal volume) may be used totrigger hypoglossal nerve stimulation. FIG. 17C schematicallyillustrates a tidal volume or inverse intrapleural pressure waveform1745. Trigger point 1746 is detected at 50% of exhalation (see comp 5FIG. 16B). Stimulation 1760 may be provided after a predetermined delay1755 from detection of trigger point 1741 (FIG. 17B) or 1746 (FIG. 17C).While 50% of exhalation is described with respect to the illustratedexamples, generally stimulation of the hypoglossal nerve is providedbefore substantial diaphragm contraction. This is done by detecting atrigger point corresponding to a preceding inspiration cycle and mostpreferably during the exhalation cycle or rest period of a precedinginspiration cycle. Alternatively, a continuous hypoglossal nervestimulation may be provided for a predetermined time, number of breaths,or may be triggered on or offAs is generally known, the EMG envelope isgenerally correlated to tidal volume. EMG amplitude is correlated torespiratory effort which increases during flow limitation and when noflow limitation exists is correlated to tidal volume.

Referring to FIGS. 18A-18F combination diaphragm/phrenic nerve, upperairway, abdominal and chest wall stimulation and respiration relatedwaveforms illustrate a stimulation device and method in accordance withthe invention.

FIG. 18A illustrates the EMG envelopes 1820 corresponding to a subject'sbreathing. FIG. 18B illustrates flow or the inverse of an upper airwaypressure waveform 1830. The upper airway pressure waveform may besensed, for example using sensor 86 positioned in the mouth. The sensedpressure corresponds to the breathing of the subject as indicated by theEMG envelope 1820 of FIG. 18A.

A low level discrete stimulation, i.e. lung volume bias stimulation 1850is applied (FIG. 18D) to the diaphragm or phrenic nerve. The biasstimulation 1850 may be provided at or during a particular portion of anintrinsic respiration cycle. For example, the bias stimulation 1850 maybe triggered at the beginning of the downward slope 1823 of the EMGenvelope 1820 (FIG. 18A), at the peak 1832 of flow or inverse of upperairway pressure 1830 (FIG. 18B), or at approximately the 50% point 1843of increasing tidal volume or inverse of intrapleural pressure 1840(FIG. 18C). These points may be determined by analyzing the waveforms,for example, as described with respect to FIGS. 16A-16E. The biasstimulation may be provided for a predetermined period of time based ona subject's innate respiration cycle. While a specific trigger point andbias stimulation duration are described with reference to FIGS. 18A-18F,the discrete bias may be timed in a number of manners. The timing of thestimulation may be determined by analyzing the respiration waveform,e.g., EMG, flow, upper airway pressure, intrapleural pressure, tidalvolume, or other respiration cycle correlated parameter, to determinethe appropriate trigger threshold. The bias stimulation may be initiatedduring a portion of an inspiration cycle, at the end of the inspirationcycle or just prior to a subsequent inspiration cycle. The biasstimulation is provided during at least a portion of the exhalationcycle. The bias stimulation 1850 may be provided until or overlappingwith the hypoglossal stimulation 1860 which is provided to open theupper airway prior to initiation of a subsequent inspiration cycle.

FIG. 18E illustrates a stimulation signal 1860 applied to thehypoglossal nerve or upper airway. In accordance with the invention, itis believed that a combined effect of providing a bias diaphragmstimulation and stimulating the upper airway or hypoglossal nerveprovides improved upper airway tonicity and/or patency. Also, inaccordance with the invention, the upper airway is preactivated prior tothe contraction of the diaphragm. Accordingly, the airway may beprepared for negative pressure caused by diaphragm contraction which mayhave a collapsing effect on the upper airway.

Stimulation of the hypoglossal nerve (or upper airway) as illustrated inFIG. 18E may be triggered a number of ways. The end 1821 of the EMGenvelope 1820 of the first breath 1825 (FIG. 18A), the zero crossingpoint 1831 of decreasing flow or inverse of upper airway pressure 1830(FIG. 18B), or the peak 1841 of tidal volume or inverse of intrapleuralpressure 1840 (FIG. 18C) may be used to trigger hypoglossal nervestimulation 1860 prior to a second breath 1826. The system may beprogrammed to wait a predetermined amount of time 1865 following thedetected end 1821 of the EMG envelope (FIG. 18A), zero crossing point1831 of decreasing flow or inverse of upper airway pressure 1830 (FIG.18B), or peak 1841 of tidal volume or inverse of intrapleural pressure1840 (FIG. 18C) to stimulate the hypoglossal nerve. The system, forexample may wait a percentage of an intrinsic exhalation period. Thisintrinsic exhalation period may be determined a number of ways. Forexample, the duration of an intrinsic inspiration period may besubtracted from the duration of an intrinsic respiration cycle. Also,the intrinsic exhalation period may be determined by measuring theduration of one or more intrinsic expiration cycles using a flowcorrelated signal or tidal volume correlated signal.

FIG. 18F illustrates a stimulation protocol of either a chest wall orabdominal muscles (muscles or associated nerves). Stimulation isprovided, e.g. using electrodes 58 or 59, to augment diaphragmstimulation. A stimulation signal 1870, may be provided prior to onsetof a subsequent inspiration, for example, during inspiration, at the endof inspiration or during exhalation.

A stimulation signal 1870 may be synchronized as illustrated byproviding stimulation a preset period 1872 following beginning of biasstimulation 1850. A stimulation signal may also be provided at some timeduring an EMG envelope 1820 or at the end 1821 of and EMG envelope (FIG.18A); during positive flow or at the beginning 1831 of negative flow ofa breath or a correlated signal (FIG. 18B); or before during or afterthe peak 1841 of tidal volume or a correlated signal (FIG. 18C). It isbelieved that such stimulation may assist in controlling lung volumeprior to a subsequent inspiration, or may assist in supplementingfunctional residual capacity. A stimulation signal 1875 may also betriggered during inspiration, e.g. at the beginning of an EMG envelope(FIG. 18A), at the beginning of positive flow or correlated signal (FIG.18B), or at the beginning of the upward slope of tidal volume or acorrelated signal (FIG. 18C). It is believed that such stimulation mayaugment diaphragm stimulation, or augment inspiration

FIGS. 19A-19E illustrate a combination diaphragm/phrenic nerve and upperairway stimulation and respiration related waveforms illustrating astimulation device and method in accordance with the invention.

Natural breathing is controlled by augmenting breathing with astimulation signal 1950 (FIG. 19D). Prior to augmentation, hypoglossalnerve (or upper airway) stimulation 1960 (FIG. 19E) is provided toprevent the upper airway from collapsing when stimulation signal 1950 isprovided.

The stimulation signal 1950 is applied to the diaphragm or phrenic nerveduring intrinsic breathing at the end of an inspiration cycle in amanner similar to that described with respect to FIGS. 6A to 6C.Stimulation may also be applied during intrinsic breathing in othermanners for various therapeutic purposes, for example, as describedherein with respect to FIGS. 4A-4D, and 10A-10C, 11A-11B, and 14A-14B.The stimulation may be triggered to be provided at or during aparticular portion of an intrinsic inspiration or respiration cycle. Thestimulation signal 1950 illustrated in FIG. 19D is triggered either atthe peak 1922 of the EMG envelope 1920 (FIG. 19A), the peak 1932 of flowor inverse airway pressure 1930 (FIG. 19B), or at about 50% 1941 oftidal volume or inverted intrapleural pressure 1940 (FIG. 19C). Thesethreshold points may be determined by analyzing the EMG, flow, upperairway pressure, tidal volume, or intrapleural pressure waveforms, forexample, in a manner set forth with respect to FIGS. 16A-16E herein.

The bias stimulation 1955 (FIG. 19D) may also be provided at other timesin the respiration cycle depending on the amount of augmented flow orinspiration duration that is desired. The low level stimulation 1955 maybe provided at times of the inspiration cycle when augmentation is notprovided. It may also be provided continuously.

FIG. 19E illustrates a stimulation signal 1960 applied to thehypoglossal nerve or upper airway. In accordance with the invention, itis believed that a combined effect of providing a stimulation to augmentor control breathing, with stimulation to the upper airway orhypoglossal nerve provides improved upper airway tonicity and/or patencythat reduces the possibility of upper airway collapse when controllingbreathing. Also, in accordance with the invention, the upper airway ispreactivated prior to the contraction of the diaphragm. Accordingly, theairway may be prepared for negative pressure caused by diaphragmcontraction particularly when stimulating to augment or controlbreathing, which may have a collapsing effect on the upper airway.

Stimulation of the hypoglossal nerve as illustrated in FIG. 19E may betriggered a number of ways. The end 1921 of the EMG envelope 1920 of thefirst breath 1925 (FIG. 19A), the zero crossing point 1931 of decreasingflow or inverse of upper airway pressure 1930 (FIG. 19B), or the peak1941 of tidal volume or inverse of intrapleural pressure 1940 (FIG. 19C)may be used to trigger hypoglossal nerve stimulation 1960 prior to asecond breath 1926. The system may be programmed to wait a predeterminedamount of time 1965 following the detected end 1921 of the EMG envelope(FIG. 19A), zero crossing point 1931 of decreasing flow or inverse ofupper airway pressure 1930 (FIG. 19B), or peak 1941 of tidal volume orinverse of intrapleural pressure 1940 (FIG. 19C) to stimulate thehypoglossal nerve. The system, for example may wait a percentage of anintrinsic exhalation period. This intrinsic exhalation period may bedetermined a number of ways. For example, the duration of an intrinsicinspiration period may be subtracted from the duration of an intrinsicrespiration cycle. Also, the intrinsic exhalation period may bedetermined by measuring the duration of one or more intrinsic expirationcycles using a flow correlated signal or tidal volume correlated signal.

Hypoglossal nerve stimulation 1960 is provided prior to onset of abreath 1926 where stimulation signal 1950 is provided. The hypoglossalnerve stimulation 1960 may also be continued for the duration of thestimulation signal 1950.

FIGS. 20A-20E illustrate a combination diaphragm/phrenic nerve and upperairway stimulation and respiration related waveforms illustrating astimulation device and method in accordance with the invention.

A stimulation signal 2050 is applied (FIG. 20D) to the diaphragm orphrenic nerve to elicit paced breathing for one or more of varioustherapeutic purposes, for example, as described herein with respect toFIGS. 5A-5C, 9A-9C and, 11A-11B, 12A-12B, 13A-13B and 14A-14B. Thestimulation may be triggered to be provided at or during a particularportion of an intrinsic inspiration or respiration cycle. As illustratedin FIG. 20D, stimulation is triggered at a time during an exhalationphase or rest period of a previous intrinsic breath 2010.

FIG. 20E illustrates a stimulation signal 2060 applied to thehypoglossal nerve or upper airway. In accordance with the invention, itis believed that a combined effect of providing a stimulation to controlbreathing with stimulation to the upper airway or hypoglossal nerveprovides improved upper airway tonicity and/or patency that reduces thepossibility of upper airway collapse when controlling breathing. Also,in accordance with the invention, the upper airway is preactivated priorto the contraction of the diaphragm. Accordingly, the airway may beprepared for negative pressure caused by diaphragm contractionparticularly when stimulating to control breathing, which may have acollapsing effect on the upper airway.

Stimulation of the hypoglossal nerve as illustrated in FIG. 20E may beinitially triggered a number of ways. FIG. 20A illustrates the sensedEMG envelope 2020 corresponding to a subject stimulated in accordancewith FIGS. 20D and 20E. The EMG signal 2020 may be processed to identifythe end 2021 of an EMG envelope corresponding to a first intrinsicbreath 2010. The end 2021 of the EMG envelope of the intrinsic breath2010 may be used to trigger combined hypoglossal nerve stimulation 2060and breathing stimulation 2050. The system may be programmed to wait tostimulate the hypoglossal nerve for a predetermined amount of time 2065following the detected end 2021 of the EMG envelope of the intrinsicbreath 2010. The system may be further programmed to wait apredetermined amount of time 2055 from the stimulation of thehypoglossal nerve to stimulate a paced breath. The zero crossing point2031 of decreasing flow or inverse of upper airway pressure 2030 (FIG.20B), or peak 2041 of tidal volume or inverse of intrapleural pressure2040 (FIG. 20C) to stimulate the hypoglossal nerve may be used astriggers as well. While specific trigger points are illustrated withrespect to FIGS. 20A-20E, a variety of other trigger points may be used.Hypoglossal stimulation 2060 preferably is provided or initiated priorto paced breathing stimulation 2050. According to one embodiment,hypoglossal stimulation 2060 is provided or initiated between 200-500 msprior to paced breathing stimulation 2050. According to another aspect,the hypoglossal nerve stimulation continues through the inspirationperiod of a paced breath (FIG. 23E).

According to another aspect of the invention, a bias stimulation 2057may be provided during an exhalation phase or rest period of the pacedbreathing. The bias stimulation 2057 may be provided for a predeterminedamount of time 2058, prior to initiation of hypoglossal stimulation2060. Alternatively the bias stimulation maybe 2057 be provided for theentire duration between paced breathing stimulation 2050.

While hypoglossal or upper airway stimulation is illustrated herein incombination with diaphragm stimulation, it is also contemplated that thehypoglossal stimulation may be provided alone and triggered to beginduring exhalation and prior to beginning of a subsequent inspirationcycle as set forth herein.

FIG. 21 schematically illustrates a device and system in accordance withthe invention. A central controller 2100 controls stimulation, forexample in accordance with one or more stimulation protocols asdescribed herein. Diaphragm stimulation 2120 is controlled by thecontroller. Hypoglossal nerve stimulation or upper airway stimulation2110 may be provided as set forth in the protocols herein to provide orincrease airway patency. The controller coordinates the timing of thehypoglossal nerve stimulation 2110 and the diaphragm stimulation 2120.Additionally or alternatively, the controller 2100 coordinatesstimulation of the chest wall 2130 and/or stimulation of theintra-abdominal muscles 2140 with diaphragm stimulation 2120 and/orhypoglossal nerve/upper airway stimulation 2110. Sensor input 2150 mayprovide information on the patient status, e.g., relating to likelihoodof onset of breathing disorder, or relating to respiration, e.g., EMG,flow or tidal volume correlated signals. This information may be used bythe controller to coordinate or control stimulation 2110, 2120, 2130,2140, for example, in accordance with one or more protocols describedherein.

The protocols set forth herein may vary or other stimulation protocolsare contemplated herein and may be used in accordance with the inventionto treat respiration related disorders.

While the invention has been described with respect to treatingobstructive sleep apnea, various aspects of the invention are notlimited to use in obstructive sleep apnea patients. The varioustechniques for controlling breathing as disclosed herein may be used inother therapeutic applications where controlling breathing is desired,for example in various breathing related disorders.

For example, stimulating breathing during intrinsic inspiration may beuseful in any treatment involving control of breathing. Stimulatingduring intrinsic inspiration may be used as a technique to graduallybegin to control or manipulate breathing parameters such as breathingrate, inspiration duration and tidal volume. Simulation during intrinsicbreathing may be used with a number of breathing control protocols toinitiate control of breathing, e.g., to gradually take over or toentrain breathing and to gradually control or manipulate breathingparameters.

The various techniques used to increase functional residual capacitymaybe used in connection with any therapy where an increase infunctional residual capacity results in a desired benefit.

Likewise, therapy described herein that stiffen the upper airway mayalso be used in any therapy for a breathing related disorder where theeffects of improving upper airway patency are beneficial.

Similarly the techniques for controlling or entraining breathing asdescribed herein may be used in other therapeutic applications wherecontrolling or entraining breathing is desired.

Similarly, techniques for creating ventilatory stability as describedherein may be used in other therapeutic application where stabilizationis beneficial.

Stimulation may be provided at various times during sleep or varioussleep stages or sleep transitions, including but not limited to, forexample: prior to sleep, at sleep onset, upon detection of droppingtidal volume, upon detection of transition into REM or non-REM or duringREM or non-REM sleep, or upon changes in breathing patterns, includingbut not limited to breathing rate.

The various stimulation protocols described herein may be combined in avariety of manners to achieve desired results.

1. A device for manipulating breathing of a subject comprising: aphrenic nerve and/or diaphragm tissue stimulation element comprising atleast a first electrode; an upper airway stimulation element comprisingat least a second electrode; a controller in communication with thefirst and second electrodes and programmed to supply a first stimulationsignal through the first electrode during at least one existing breathto a phrenic nerve and/or diaphragm tissue to elicit a diaphragmresponse without initiating a new breath during a respiratory cycle ofthe subject having intrinsic respiration and to further supply a secondstimulation signal through the second electrode during at least oneexisting breath to tissue associated with an upper airway of the subjectduring said respiratory cycle to elicit a response of an upper airwaymusculature; and, a sensor in communication with the controller, whereinthe sensor is configured to detect at least one parameter of therespiratory cycle, wherein the controller is further programmed tocoordinate the first and second stimulation signals provided by thephrenic nerve and/or diaphragm tissue stimulation element and upperairway stimulation element with respect to each other to supplydiaphragm stimulation and upper airway stimulation such that the breathis supplemented, and wherein the controller is also programmed to adjusta waveform of the first stimulation signal in response to the sensedparameter of the respiratory cycle.
 2. The device of claim 1 wherein thecontroller is further programmed to stimulate the upper airway via theupper airway stimulation element during a first respiratory cycle priorto inspiration of a next respiratory cycle.
 3. The device of claim 2wherein the controller is further programmed to stimulate the upperairway via the upper airway stimulation element during an exhalationcycle of a first respiratory cycle prior to inspiration of the nextrespiratory cycle.
 4. The device of claim 3 wherein the controller isfurther programmed to provide the first stimulation signal via thephrenic nerve and/or diaphragm tissue stimulation element to stabilizean airway and a subsequent stimulation signal via the phrenic nerveand/or diaphragm tissue stimulation element.
 5. The device of claim 4wherein the controller is further programmed to provide an increasedlung volume beyond a baseline via the phrenic nerve and/or diaphragmtissue stimulation element.
 6. The device of claim 1 wherein thecontroller is further programmed to provide stimulation via the phrenicnerve and/or diaphragm tissue stimulation element to supplement anintrinsic breath of said next respiratory cycle.
 7. The device of claim1 wherein the controller is further programmed to increase a functionalresidual capacity of the subject by providing a stimulation via thephrenic nerve and/or diaphragm tissue stimulation element whilestiffening the airway.
 8. The device of claim 1 wherein the controlleris further programmed to provide stimulation via the diaphragmstimulation element to augment or supplement a tidal volume of theintrinsic respiration of a subsequent respiratory cycle.
 9. The deviceof claim 1 wherein the controller is further programmed to providestimulation via the phrenic nerve and/or diaphragm tissue stimulationelement to increase lung volume.
 10. A device for manipulating breathingof a subject comprising: a phrenic nerve and/or diaphragm tissuestimulation element comprising at least a first electrode; an upperairway stimulation element comprising at least a second electrode; acontroller in communication with the first and second electrodes andprogrammed to supply a low-level stimulation signal through the firstelectrode during at least one existing breath to a phrenic nerve and/ordiaphragm tissue of the subject having intrinsic respiration to elicit adiaphragm response without initiating a new breath and to further supplya stimulation signal through the second electrode during at least oneexisting breath to tissue associated with an upper airway of the subjectto elicit a response of an upper airway musculature; and, a sensor incommunication with the controller, wherein the sensor is configured todetect at least one parameter of the respiratory cycle, wherein thecontroller is further programmed to coordinate the first and secondstimulation signals provided by the phrenic nerve and/or diaphragmtissue stimulation element and upper airway stimulation element withrespect to each other to supply diaphragm stimulation and upper airwaystimulation such that the functional residual capacity is supplemented,and wherein the controller is also programmed to adjust a waveform ofthe first stimulation signal in response to the sensed parameter of therespiratory cycle.
 11. The device of claim 10 wherein the controller isfurther programmed to supply an electrical stimulation signal via theupper airway stimulation element during an exhalation portion of a firstrespiratory cycle prior to an inspiration portion of an inspirationportion of a next respiratory cycle.
 12. The device of claim 10 whereinthe controller is further programmed to provide the low-levelstimulation signal via the phrenic nerve and/or diaphragm tissuestimulation element to stabilize an airway and a subsequent stimulationsignal via the phrenic nerve and/or diaphragm tissue stimulation elementto elicit a breath.
 13. A device for manipulating breathing of a subjectcomprising: a phrenic nerve and/or diaphragm tissue stimulation elementcomprising at least a first electrode; an auxiliary stimulation elementcomprising at least a second electrode; a controller in communicationwith the first and second electrodes and programmed to supply astimulation signal through the first electrode during at least oneexisting breath to a phrenic nerve and/or diaphragm tissue of thesubject having intrinsic respiration to elicit a diaphragm responsewithout initiating a new breath during a respiratory cycle of thesubject and to further supply a stimulation signal through the secondelectrode during at least one existing breath to tissue associated withan auxiliary musculature associated with the subject's respiratorysystem during said respiratory cycle to elicit an auxiliary response ofthe auxiliary musculature; and, a sensor in communication with thecontroller, wherein the sensor is configured to detect at least oneparameter of the respiratory cycle, wherein the controller is furtherprogrammed to coordinate the first and second stimulation signalsprovided by the phrenic nerve and/or diaphragm tissue stimulationelement and auxiliary stimulation element with respect to each other tosupply diaphragm stimulation and auxiliary stimulation such that thebreath is augmented, and wherein the controller is also programmed toadjust a waveform of the first stimulation signal in response to thesensed parameter of the respiratory cycle.
 14. A method for manipulatingbreathing of a subject comprising the steps of: providing a phrenicnerve and/or diaphragm tissue stimulation element comprising at least afirst electrode and an upper airway stimulation element comprising atleast a second electrode; monitoring a respiratory parameter of thesubject; supplying a first stimulation signal through the firstelectrode during an existing breath to a phrenic nerve and/or diaphragmtissue of the subject to elicit a diaphragm response without initiatinga new breath during intrinsic respiration of the subject, wherein thefirst stimulation signal has a waveform which elicits the diaphragmresponse and which is adjusted in response to the monitored respiratoryparameter; supplying a second stimulation signal through the secondelectrode during the existing breath to tissue associated with an upperairway of the subject to elicit a response of an upper airwaymusculature; and coordinating the first and second stimulation signalsrespectively provided by the diaphragm stimulation element and upperairway stimulation element to avoid upper airway collapse duringdiaphragm stimulation such that the breath is supplemented.
 15. A methodfor manipulating breathing of a subject comprising the steps of:providing a phrenic nerve and/or diaphragm tissue stimulation elementcomprising at least a first electrode and an upper airway stimulationelement comprising at least a second electrode; monitoring a respiratoryparameter of the subject; supplying a first stimulation signal throughthe first electrode during an existing breath to a phrenic nerve and/ordiaphragm tissue of the subject to elicit a diaphragm response withoutinitiating a new breath during intrinsic respiration of the subject,wherein the first stimulation signal has a waveform which elicits thediaphragm response and which is adjusted in response to the monitoredrespiratory parameter; supplying a second stimulation signal through thesecond electrode during the existing breath to tissue associated with anupper airway of the subject to elicit a response of an upper airwaymusculature; and stimulating the upper airway musculature during anexhalation cycle of a first respiratory cycle prior to an inspirationportion of a next respiratory cycle.
 16. The method of claim 15 whereinthe step of supplying a first stimulation signal comprises eliciting thediaphragm response by augmenting an intrinsic breath.
 17. The method ofclaim 16 wherein the step of augmenting an intrinsic breath comprisesaugmenting the breath during said next respiration cycle.
 18. The methodof claim 15 wherein the step of supplying a first stimulation signalcomprises eliciting the diaphragm response by providing a lung volumebias stimulation without eliciting a respiratory cycle.
 19. A method formanipulating breathing of a subject comprising the steps of: providing aphrenic nerve and/or diaphragm tissue stimulation element comprising atleast a first electrode and an auxiliary stimulation element comprisingat least a second electrode; monitoring a respiratory parameter of thesubject; supplying a first stimulation signal through the firstelectrode during an existing breath to a phrenic nerve and/or diaphragmtissue to elicit a diaphragm response without initiating a new breathduring a respiratory cycle of the subject having intrinsic respiration,wherein the first stimulation signal has a waveform which elicits thediaphragm response and which is adjusted in response to the monitoredrespiratory parameter; supplying a second stimulation signal through thesecond electrode during the existing breath to tissue associated with anauxiliary musculature associated with the subject's respiratory systemduring said respiratory cycle to elicit an auxiliary response of anauxiliary musculature; and coordinating the first and second stimulationsignals respectively provided by the diaphragm stimulation element andauxiliary stimulation element with respect to each other such that thebreath is augmented.
 20. The method for manipulating breathing of claim19 wherein the step of coordinating the first and second stimulationsignals comprises coordinating the diaphragm stimulation with one ormore of upper airway stimulation, chest wall stimulation and abdominalstimulation.